Abstract
Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) phosphorylation drives HER2-positive breast cancer cell proliferation. Enforced activation of phosphatases for those receptors could be a therapeutic option for HER2-positive breast cancers. Here, we report that degradation of an endosomal small GTPase, RhoB, by the ubiquitin ligase complex cullin-3 (CUL3)/KCTD10 is essential for both EGFR and HER2 phosphorylation in HER2-positive breast cancer cells. Using human protein arrays produced in a wheat cell-free protein synthesis system, RhoB-GTP, and protein tyrosine phosphatase receptor type H (PTPRH) were identified as interacting proteins of connector enhancer of kinase suppressor of Ras1 (CNKSR1). Mechanistically, constitutive degradation of RhoB, which is mediated by the CUL3/KCTD10 E3 complex, enabled CNKSR1 to interact with PTPRH at the plasma membrane resulting in inactivation of EGFR phosphatase activity. Depletion of CUL3 or KCTD10 led to the accumulation of RhoB-GTP at the plasma membrane followed by its interaction with CNKSR1, which released activated PTPRH from CNKSR1. This study suggests a mechanism of PTPRH activation through the exclusive binding of RhoB-GTP to CNKSR1.
Highlights
Inactivation of receptor tyrosine kinases is mainly achieved through their dephosphorylation by protein tyrosine phosphatases
Knockdown of CUL3 or KCTD10 reduced the phosphorylation of both epidermal growth factor receptor (EGFR) and HER2 in connector enhancer of kinase suppressor of Ras1 (CNKSR1) (W493A) mutant-expressing SKBR-3 cells, as seen in control and wild-type CNKSR1-expressing SKBR-3 cells (Fig 6E)
Our result indicated that the depletion of CUL3 or KCTD10 caused the accumulation of RhoB protein in HER2-positive breast cancer cells
Summary
Inactivation of receptor tyrosine kinases is mainly achieved through their dephosphorylation by protein tyrosine phosphatases. Protein tyrosine phosphatases generally act as tumor suppressors by terminating signal transduction from phosphorylated oncogenic receptor tyrosine kinases (Bollu et al, 2017). Several protein tyrosine phosphatases such as PTPN11 (alias SHP2) and PTP4A3 function as oncogenes (Bunda et al, 2015; den Hollander et al, 2016). Another protein tyrosine phosphatase, PTPN1, acts as a tumor suppressor in lymphomagenesis or an oncoprotein in breast cancers and non–small cell lung cancers (Dubeet al, 2005; Julien et al, 2007). Because the activation of protein tyrosine phosphatases could principally reduce the phosphorylation of receptor tyrosine kinases leading to the suppression of cell growth, the forced activation of protein tyrosine phosphatases targeting EGFR and/or HER2 could be new strategy for HER2positive breast cancer therapies
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
